A genetic compensatory mechanism regulated by <i>Jun</i> and <i>Mef2d</i> modulates the expression of distinct class IIa <i>Hdacs</i> to ensure peripheral nerve myelination and repair.

Abstract

The class IIa histone deacetylases (HDACs) have pivotal roles in the development of different tissues. Of this family, Schwann cells express <i>Hdac4</i>, <i>5</i>, and <i>7</i> but not <i>Hdac9</i>. Here, we show that a transcription factor regulated genetic compensatory mechanism within this family of proteins, blocks negative regulators of myelination ensuring peripheral nerve developmental myelination and remyelination after injury. Thus, when <i>Hdac4</i> and <i>5</i> are knocked-out from Schwann cells in mice, a JUN-dependent mechanism induces the compensatory overexpression of <i>Hdac7</i> permitting, although with a delay, the formation of the myelin sheath. When <i>Hdac4</i>, <i>5</i>, and <i>7</i> are simultaneously removed, the myocyte-specific enhancer-factor d (MEF2D) binds to the promoter and induces the de novo expression of <i>Hdac9</i>, and although several melanocytic lineage genes are misexpressed and Remak bundle structure is disrupted, myelination proceeds after a long delay. Thus, our data unveil a finely tuned compensatory mechanism within the class IIa <i>Hdac</i> family, coordinated by distinct transcription factors, that guarantees the ability of Schwann cells to myelinate during development and remyelinate after nerve injury.